tbuckley/cabot-search huggingface dataset:
A multi-specific, multi-affinity antibody platform neutralizes sarbecoviruses and confers protection against SARS-CoV-2 in vivo
Authors: Clare Burn Aschner, Krithika Muthuraman, Iga Kucharska, Hong Cui, Katherine Prieto, Manoj S. Nair, Maple Wang, Yaoxing Huang, Natasha Christie-Holmes, Betty Poon, Jessica Lam, Azmiri Sultana, Robert Kozak, Samira Mubareka, John L. Rubinstein, Edurne Rujas, Bebhinn Treanor, David D. Ho, Arif Jetha, Jean-Philippe Julien
Journal: Science Translational Medicine (2023)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been responsible for a global pandemic. Monoclonal antibodies (mAbs) have been used as antiviral therapeutics; however, these therapeutics have been limited in efficacy by viral sequence variability in emerging variants of concern (VOCs) and in deployment by the need for high doses. In this study, we leveraged the multi-specific, multi-affinity antibody (Multabody, MB) platform, derived from the human apoferritin protomer, to enable the multimerization of antibody fragments. MBs were shown to be highly potent, neutralizing SARS-CoV-2 at lower concentrations than their corresponding mAb counterparts. In mice infected with SARS-CoV-2, a tri-specific MB targeting three regions within the SARS-CoV-2 receptor binding domain was protective at a 30-fold lower dose than a cocktail of the corresponding mAbs. Furthermore, we showed in vitro that mono-specific MBs potently neutralize SARS-CoV-2 VOCs by leveraging augmented avidity, even when corresponding mAbs lose their ability to neutralize potently, and that tri-specific MBs expanded the neutralization breadth beyond SARS-CoV-2 to other sarbecoviruses. Our work demonstrates how avidity and multi-specificity combined can be leveraged to confer protection and resilience against viral diversity that exceeds that of traditional monoclonal antibody therapies.
Non–muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Guérin
Authors: Florus C. de Jong, Teemu D. Laajala, Robert F. Hoedemaeker, Kimberley R. Jordan, Angelique C. J. van der Made, Egbert R. Boevé, Deric K. E. van der Schoot, Bart Nieuwkamer, Emiel A. M. Janssen, Tokameh Mahmoudi, Joost L. Boormans, Dan Theodorescu, James C. Costello, Tahlita C. M. Zuiverloon
Journal: Science Translational Medicine (2023)

The recommended treatment for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. If progression to advanced disease occurs, then patients must undergo a radical cystectomy with risks of substantial morbidity and poor clinical outcome. Identifying tumors unlikely to respond to BCG can translate into alternative treatments, such as early radical cystectomy, targeted therapies, or immunotherapies. Here, we conducted molecular profiling of 132 patients with BCG-naive HR-NMIBC and 44 patients with recurrences after BCG (34 matched), which uncovered three distinct BCG response subtypes (BRS1, 2 and BRS3). Patients with BRS3 tumors had a reduced recurrence-free and progression-free survival compared with BRS1/2. BRS3 tumors expressed high epithelial-to-mesenchymal transition and basal markers and had an immunosuppressive profile, which was confirmed with spatial proteomics. Tumors that recurred after BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive patients with HR-NMIBC, and the molecular subtypes outperformed guideline-recommended risk stratification based on clinicopathological variables. For clinical application, we confirmed that a commercially approved assay was able to predict BRS3 tumors with an area under the curve of 0.87. These BCG response subtypes will allow for improved identification of patients with HR-NMIBC at the highest risk of progression and have the potential to be used to select more appropriate treatments for patients unlikely to respond to BCG.
A meta-analysis suggests that tACS improves cognition in healthy, aging, and psychiatric populations
Authors: Shrey Grover, Renata Fayzullina, Breanna M. Bullard, Victoria Levina, Robert M. G. Reinhart
Journal: Science Translational Medicine (2023)

Transcranial alternating current stimulation (tACS) has attracted interest as a technique for causal investigations into how rhythmic fluctuations in brain neural activity influence cognition and for promoting cognitive rehabilitation. We conducted a systematic review and meta-analysis of the effects of tACS on cognitive function across 102 published studies, which included 2893 individuals in healthy, aging, and neuropsychiatric populations. A total of 304 effects were extracted from these 102 studies. We found modest to moderate improvements in cognitive function with tACS treatment that were evident in several cognitive domains, including working memory, long-term memory, attention, executive control, and fluid intelligence. Improvements in cognitive function were generally stronger after completion of tACS ("offline" effects) than during tACS treatment ("online" effects). Improvements in cognitive function were greater in studies that used current flow models to optimize or confirm neuromodulation targets by stimulating electric fields generated in the brain by tACS protocols. In studies targeting multiple brain regions concurrently, cognitive function changed bidirectionally (improved or decreased) according to the relative phase, or alignment, of the alternating current in the two brain regions (in phase versus antiphase). We also noted improvements in cognitive function separately in older adults and in individuals with neuropsychiatric illnesses. Overall, our findings contribute to the debate surrounding the effectiveness of tACS for cognitive rehabilitation, quantitatively demonstrate its potential, and indicate further directions for optimal tACS clinical study design.
Targeted delivery of tumor necrosis factor in combination with CCNU induces a T cell–dependent regression of glioblastoma
Authors: Thomas Look, Emanuele Puca, Marcel Bühler, Daniel Kirschenbaum, Roberto De Luca, Riccardo Stucchi, Domenico Ravazza, Cesare Di Nitto, Patrick Roth, Yonatan Katzenelenbogen, Assaf Weiner, Lukas Rindlisbacher, Burkhard Becher, Ido Amit, Michael Weller, Dario Neri, Teresa Hemmerle, Tobias Weiss
Journal: Science Translational Medicine (2023)

Glioblastoma is the most aggressive primary brain tumor with an unmet need for more effective therapies. Here, we investigated combination therapies based on L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively localizes to cancer neovasculature. Using immunocompetent orthotopic glioma mouse models, we identified strong anti-glioma activity of L19TNF in combination with the alkylating agent CCNU, which cured the majority of tumor-bearing mice, whereas monotherapies only had limited efficacy. In situ and ex vivo immunophenotypic and molecular profiling in the mouse models revealed that L19TNF and CCNU induced tumor DNA damage and treatment-associated tumor necrosis. In addition, this combination also up-regulated tumor endothelial cell adhesion molecules, promoted the infiltration of immune cells into the tumor, induced immunostimulatory pathways, and decreased immunosuppression pathways. MHC immunopeptidomics demonstrated that L19TNF and CCNU increased antigen presentation on MHC class I molecules. The antitumor activity was T cell dependent and completely abrogated in immunodeficient mouse models. On the basis of these encouraging results, we translated this treatment combination to patients with glioblastoma. The clinical translation is ongoing but already shows objective responses in three of five patients in the first recurrent glioblastoma patient cohort treated with L19TNF in combination with CCNU (NCT04573192).
Global Control of Meningococcal Disease
Authors: David S. Stephens
Journal: New England Journal of Medicine (2023)

The exclusively human pathogen Neisseria meningitidis, which was first described in 1805 after an outbreak of 33 cases in Geneva, Switzerland, has been feared worldwide for more than 215 years as a cause of epidemics, pandemics, and sporadic cases of meningitis, rapidly fatal sepsis, and less commonly, pneumonia, often in otherwise-healthy young persons.1-3 Although disease rates have been decreasing in many regions of the world owing in part to the introduction of highly effective vaccines,4 case fatality remains high at 10 to 20%, and 11 to 19% of persons who survive infection have long-term consequences such as neurologic disabilities, sensory . . .
Case 16-2023: A 13-Year-Old Boy with Depression and Hypotension
Authors: Kevin R. Schwartz, Abigail L. Donovan, Bryan D. Hayes, Mai Uchida, Joy B. Rosen
Journal: New England Journal of Medicine (2023)

A 13-year-old boy presented with depression and suicidality. An episode of hypertension occurred, followed by hypotension in the context of a normal heart rate. A diagnosis was made.
Time to Treat Severe Community-Acquired Pneumonia with Steroids?
Authors: Joshua P. Metlay, Grant W. Waterer
Journal: New England Journal of Medicine (2023)

Guidelines for the treatment of community-acquired pneumonia (CAP) focus primarily on the choice of antibiotic therapy. However, the 2019 guidelines of the American Thoracic Society and the Infectious Diseases Society of America for adult CAP was the first version to address the role of glucocorticoids as adjunct therapy. The guideline committee (which we cochaired) did not recommend the use of glucocorticoids for most patients with CAP,1 but it did endorse the use of glucocorticoids for adults with refractory septic shock that is resistant to fluid resuscitation and vasopressor support, consistent with the suggested use of these drugs in previously released . . .
Engineering Extracellular Matrix‐Bound Nanovesicles Secreted by Three‐Dimensional Human Mesenchymal Stem Cells
Authors: Chang Liu, Xingchi Chen, Yuan Liu, Li Sun, Zhibin Yu, Yi Ren, Changchun Zeng, Yan Li
Journal: Advanced Healthcare Materials (2023)

Extracellular matrix (ECM) in the human tissue contains vesicles, which are defined as matrix-bound nanovesicles (MBVs). MBVs serve as one of the functional components in ECM, recapitulating part of the regulatory roles and in vivo microenvironment. In this study, extracellular vesicles from culture supernatants (SuEVs) and MBVs are isolated from the conditioned medium or ECM, respectively, of 3D human mesenchymal stem cells. Nanoparticle tracking analysis shows that MBVs are smaller than SuEVs (100-150 nm). Transmission electron microscopy captures the typical cup shape morphology for both SuEVs and MBVs. Western blot reveals that MBVs have low detection of some SuEV markers such as syntenin-1. miRNA analysis of MBVs shows that 3D microenvironment enhances the expression of miRNAs such as miR-19a and miR-21. In vitro functional analysis shows that MBVs can facilitate human pluripotent stem cell-derived forebrain organoid recovery after starvation and promote high passage fibroblast proliferation. In macrophage polarization, 2D MBVs tend to suppress the pro-inflammatory cytokine IL-12β, while 3D MBVs tend to enhance the anti-inflammatory cytokine IL-10. This study has the significance in advancing the understanding of the bio-interface of nanovesicles with human tissue and the design of cell-free therapy for treating neurological disorders such as ischemic stroke.
Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression
Authors: Amit Anand, Sanjay J. Mathew, Gerard Sanacora, James W. Murrough, Fernando S. Goes, Murat Altinay, Amy S. Aloysi, Ali A. Asghar-Ali, Brian S. Barnett, Lee C. Chang, Katherine A. Collins, Sara Costi, Sidra Iqbal, Manish K. Jha, Kamini Krishnan, Donald A. Malone, Sina Nikayin, Steven E. Nissen, Robert B. Ostroff, Irving M. Reti, Samuel T. Wilkinson, Kathy Wolski, Bo Hu
Journal: New England Journal of Medicine (2023)

Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain.We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period.A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation.Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).
Ketamine and ECT in Depression — Risks and Rewards
Authors: Robert Freedman
Journal: New England Journal of Medicine (2023)

Investigators from five referral clinics for electroconvulsive therapy (ECT) report in the Journal the results of an open-label, randomized, noninferiority trial of ECT or ketamine infusion in patients with moderately severe depression.1 After randomization, 365 patients (170 in the ECT group and 195 in the ketamine group) were included in the primary analysis. At the conclusion of the 3-week, randomized, active-treatment phase, 41% of the patients in the ECT group and 55% of those in the ketamine group reported a 50% or greater reduction in symptoms, findings that are consistent with moderate-to-excellent responses to treatment.2 Patients who had a response . . .
Patient and Carer Experiences with Bladder Cancer: Results from a Global Survey in 45 Countries
Authors: Lydia E. Makaroff, Alex Filicevas, Shannon Boldon, Patrick Hensley, Peter C. Black, Stephanie Chisolm, Stephanie Demkiw, Mario I. Fernández, Mikio Sugimoto, Bente Thoft Jensen, Wim P.J. Witjes, Ken Bagshaw, Lori Cirefice-Funk, Allen Knight, Ashish M. Kamat
Journal: European Urology (2023)
Effect of Canagliflozin on Heart Failure Hospitalization in Diabetes According to Baseline Heart Failure Risk
Authors: Muhammad Shahzeb Khan, Matthew W. Segar, Muhammad Shariq Usman, Kershaw V. Patel, Harriette G.C. Van Spall, Adam D. DeVore, Muthiah Vaduganathan, Carolyn S.P. Lam, Faiez Zannad, Subodh Verma, Javed Butler, W.H. Wilson Tang, Ambarish Pandey
Journal: JACC Heart Failure (2023)
When Does a Calcium Score Equate to Secondary Prevention?
Authors: Matthew J. Budoff, April Kinninger, Heidi Gransar, Stephan Achenbach, Mouaz Al-Mallah, Jeroen J. Bax, Daniel S. Berman, Filippo Cademartiri, Tracy Q. Callister, Hyuk-Jae Chang, Benjamin J.W. Chow, Ricardo C. Cury, Gudrun Feuchtner, Martin Hadamitzky, Joerg Hausleiter, Philipp A. Kaufmann, Jonathon Leipsic, Fay Y. Lin, Yong-Jin Kim, Hugo Marques, Gianluca Pontone, Ronen Rubinshtein, Leslee J. Shaw, Todd C. Villines, James K. Min
Journal: JACC. Cardiovascular imaging (2023)
Myocardial Inflammation and Fibrosis Are Associated With Reduced Strain in Collegiate Athletes Recovering From SARS-CoV-2
Authors: John L. Heyniger, Katarzyna E. Gil, Brett G. Klamer, Kan N. Hor, Simon Lee, Lauren Ledingham, Matthew S. Tong, Curt J. Daniels, Orlando P. Simonetti, Saurabh Rajpal
Journal: JACC. Cardiovascular imaging (2023)
Cardiac Magnetic Resonance for Prophylactic Implantable-Cardioverter Defibrillator Therapy in Ischemic Cardiomyopathy
Authors: Gianluca Pontone, Andrea Igoren Guaricci, Laura Fusini, Andrea Baggiano, Marco Guglielmo, Giuseppe Muscogiuri, Alessandra Volpe, Raffaele Abete, Giovanni Aquaro, Andrea Barison, Jan Bogaert, Giovanni Camastra, Samuela Carigi, Nazario Carrabba, Grazia Casavecchia, Stefano Censi, Gloria Cicala, Carlo N. De Cecco, Manuel De Lazzari, Gabriella Di Giovine, Mauro Di Roma, Monica Dobrovie, Marta Focardi, Nicola Gaibazzi, Annalaura Gismondi, Matteo Gravina, Chiara Lanzillo, Massimo Lombardi, Valentina Lorenzoni, Jordi Lozano-Torres, Chiara Martini, Francesca Marzo, Ambra Masi, Riccardo Memeo, Claudio Moro, Alberto Nese, Alessandro Palumbo, Anna Giulia Pavon, Patrizia Pedrotti, Martina Perazzolo Marra, Silvia Pica, Silvia Pradella, Cristina Presicci, Mark G. Rabbat, Claudia Raineri, José F. Rodriguez-Palomares, Stefano Sbarbati, U. Joseph Schoepf, Angelo Squeri, Nicola Sverzellati, Rolf Symons, Emily Tat, Mauro Timpani, Giancarlo Todiere, Adele Valentini, Akos Varga-Szemes, Pier-Giorgio Masci, Juerg Schwitter
Journal: JACC. Cardiovascular imaging (2023)
Renin-independent aldosteronism and chronic kidney disease in diabetes: Observational and Mendelian randomization analyses
Authors: Jinbo Hu, Xiangjun Chen, Yi Luo, Jun Yang, Qinglian Zeng, Wenjin Luo, Xiaoyu Shu, Qingfeng Cheng, Lilin Gong, Zhihong Wang, Qifu Li, Shumin Yang
Journal: Metabolism (2023)
High proportion of H3 avian influenza virus circulating in chickens – An increasing threat to public health
Authors: Tianyi Zhao, Yitao Li, Mingguo Xu, Wenjing Wang, Shuyang Li, Xingwang Cao, Ningyi Fuxiang, Yong Wang, Yaling Li, Hui Zhang, Chencheng Xiao
Journal: Journal of Infection (2023)
Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study
Authors: Shun Lu, Jianying Zhou, Hong Jian, Lin Wu, Ying Cheng, Yun Fan, Jian Fang, Gongyan Chen, Zhihong Zhang, Dongqing Lv, Liyan Jiang, Rong Wu, Xiangming Jin, Xiaodong Zhang, Junhong Zhang, Conghua Xie, Gengyun Sun, Dongning Huang, Jiuwei Cui, Renhua Guo, Zhigang Han, Zhendong Chen, Jin Liang, Wu Zhuang, Xingsheng Hu, Aimin Zang, Yi Zhang, Shundong Cang, Yuanbo Lan, Xi Chen, Laiyu Liu, Xingya Li, Jun Chen, Rui Ma, Yanzhen Guo, Ping Sun, Panwen Tian, Yueyin Pan, Zhe Liu, Peiguo Cao, Lieming Ding, Yang Wang, Xiaobin Yuan, Pengxiang Wu
Journal: The Lancet Respiratory Medicine (2023)
Novel anemia therapies in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Authors: Elaine Ku, Lucia Del Vecchio, Kai-Uwe Eckardt, Volker H. Haase, Kirsten L. Johansen, Masaomi Nangaku, Navdeep Tangri, Sushrut S. Waikar, Andrzej Więcek, Michael Cheung, Michel Jadoul, Wolfgang C. Winkelmayer, David C. Wheeler, Baris Afsar, Tadao Akizawa, Stefan D. Anker, Mustafa Arici, Jodie L. Babitt, Jonathan Barratt, Jeffrey S. Berns, Anatole Besarab, Sunil Bhandari, Christopher Brown, Aleix Cases, Glenn M. Chertow, Cynthia Delgado, Tillman B. Drüeke, Steven Fishbane, Rafael Gómez, Morgan E. Grams, Takayuki Hamano, Chuan-Ming Hao, Raymond K. Hsu, Kunitoshi Iseki, Isabelle Jordans, Edgar V. Lerma, Francesco Locatelli, Iain C. Macdougall, Jolanta Małyszko, Patrick Maxwell, Lawrence P. McMahon, Gregorio T. Obrador, Marlies Ostermann, Roberto Pecoits-Filho, Farzana Perwad, Simon D. Roger, Ajay K. Singh, Laura Solá, Bruce S. Spinowitz, Mai Sugahara, Toshiyuki Takahashi, Mototsugu Tanaka, Tetsuhiro Tanaka, Der-Cherng Tarng, Marcello Tonelli, Yusuke Tsukamoto, Carl P. Walther, Angela Yee-Moon Wang, Hong Kong, Bradley A. Warady, Angela C. Webster, Matthew R. Weir, Jay B. Wish, Muh Geot Wong
Journal: Kidney International (2023)

Anemia is common in patients with chronic kidney disease (CKD) and is associated with a high burden of morbidity and adverse clinical outcomes. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline for the diagnosis and management of anemia in CKD. Since then, new data from studies assessing established and emerging therapies for the treatment of anemia and iron deficiency have become available. Beginning in 2019, KDIGO planned two Controversies Conferences to review the new evidence and its potential impact on the management of anemia in clinical practice. Here we report on the second of these conferences held virtually in December 2021 which focused on a new class of agents, the hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs). This report provides a review of the consensus points and controversies from this second conference and highlights areas that warrant prioritization for future research.
Acute respiratory failure-related excess mortality in pediatric sepsis
Authors: Garrett Keim, Andrew G Percy, Adam S Himebauch, Jesse Y Hsu, Jason D Christie, Nadir Yehya
Journal: Thorax (2023)

Excess mortality risk imparted by acute respiratory failure in children is unknown. We determined excess mortality risk associated with mechanically ventilated acute respiratory failure in pediatric sepsis. Novel ICD10-based algorithms were derived and validated to identify a surrogate for acute respiratory distress syndrome to calculate excess mortality risk. Algorithm-identified ARDS was identified with specificity of 96.7% (CI 93.0 − 98.9) and sensitivity of 70.5% (CI 44.0 – 89.7). Excess risk of mortality for ARDS was 24.4% (CI 22.9 – 26.2). Development of ARDS requiring mechanical ventilation imparts modest excess risk of mortality in septic children.